Vaccination plays an important role in preventing infectious diseases and is therefore a possible solution for biological warfare. The fixed nature of the traditional vaccine is a major limitation to its success. Some pathogens, such as HIV, SARS, influenza, and hepatitis C naturally mutate and others may be deliberately mutated for military uses. Because immune responses typically develop much more slowly than new variants, mutated pathogens can escape control by vaccination and rapidly generate epidemics. The current strategy calls for immunizing against every newly identified pathogen. However, since it is not possible to predict which variants will be deliberately generated for biological warfare, repeated vaccination cannot proactively protect against "new" pathogens. The proposed research will test a novel type of vaccine that will trigger immune responses directed against antigenic variants in anticipation of pathogen diversification, the mutable vaccine. A mutable vaccine is a DNA vaccine in which the gene coding for the antigen is caused to mutate a million times more frequently than a typical gene, at a rate comparable to that of a mutable virus. Because the appearance of mutant antigens will anticipate the appearance of variants, a mutant pathogen is less likely to evade the immune response. The overall goal is to demonstrate the proof of principle for the mutable vaccine. For this end influenza is used as a model. A vector encoding a mutable influenza hemagglutinin (HA) gene will be produced and ability to generate HA antigenic variants will be tested. The vaccine will then be tested for ability to promote an immune response against antigenic variants of influenza.